CA3103168A1

CA3103168A1 - Stopper device, medicament container, and method for mixing two substances in a medicament container

Info

Publication number: CA3103168A1
Application number: CA3103168A
Authority: CA
Inventors: Fatbardha Messner-Rugova; Markus EGGENSBERGER
Original assignee: Vetter Pharma Fertigung GmbH and Co KG
Current assignee: Vetter Pharma Fertigung GmbH and Co KG
Priority date: 2018-07-03
Filing date: 2019-06-28
Publication date: 2020-01-09
Also published as: JP7361059B2; JP2021529063A; BR112020026344A2; US20210113433A1; EP3817706A1; WO2020007752A1; DE102018210941A1; MX2020013909A

Abstract

The invention relates to a stopper device (1) for sealing off a medicament container (45) with a stopper element (3), wherein the stopper device is designed to seal off the medicament container (45) in an axial direction of a centre axis (M) of the medicament container (45), wherein the stopper device (1) is at least partially insertable into the medicament container (45), and the stopper element (3), in the intended installation position in the medicament container (45), is displaceable along the centre axis (M) of the medicament container (45). Provision is made that the stopper device (1) has a retention region (23) with at least one retention means (5), wherein a closure element (7), in a first functional state of the stopper device (1), is retained by the retention means (5) in a fixed position relative to the stopper element (3), in particular retained releasably in a retention position on the stopper element (3), in such a way that a cavity (29) is formed between the closure element (7) and the stopper element (3).

Description

2 CA 03103168 2020-12-09 DESCRIPTION
Stopper device, medicament container, and method for mixing two substances in a medicament container The invention relates to a stopper device, a medicament container having such a stopper device, and a method for mixing two substances that are stored separately from one another in terms of flow in such a medicament container.
Stopper devices, medicament containers, and methods of the type discussed here are known.
Two substances stored separately from one another in terms of flow are typically mixed with one another in a medicament container embodied as a two-chamber system. A first substance of the two substances is arranged in a first, proximal chamber and a second substance is arranged in a second, distal chamber.
In such a medicament container, the first, proximal chamber is delimited in the proximal direction by a first stopper device, in particular an end stopper, in the distal direction by a second stopper device, especially a center stopper, and in the radial direction by an inner wall of the medicament container. The second, distal chamber is delimited in the proximal direction by the second stopper device, in the radial direction by the inner wall of the medicament container, and in the distal direction by the medicament container tip, which is preferably closed by a closure cap.
Before the medicament container is initialized, the proximal chamber is closed in a fluidically tight manner with respect to the distal chamber and the surroundings of the medicament container. The second stopper device is not shifted into a mixing position until initialization, which establishes a fluidic connection between the two chambers via a bypass, so that the two substances can mix with one another, provided the second stopper device is arranged in the mixing position. In particular, by exerting an in particular manual pressure on the first stopper device, the contents of the proximal chamber, that is, the first substance, are pressed out of the proximal chamber and transported into the distal chamber via the bypass, the volume of the Date Recue/Date Received 2020-12-09 proximal chamber being reduced and the second stopper device remaining in the mixing position until the first stopper device butts against the second stopper device.
The initialization thus includes application of pressure to the first stopper device in the distal direction, causing displacement of the first stopper device. Due to the displacement and the fluidic sealing off of the proximal chamber, pressure is also applied to the second stopper device, so that the latter is also displaced in the distal direction until it reaches the mixing position. In the mixing position, the bypass causes the pressure to equalize, so that the second stopper device is no longer subjected to the pressure on one side. In such conventional medicament containers, for initialization and thus for mixing the two substances, it is therefore necessary for both stopper devices to be displaced.
Before the initialization, that is, before the use of the known method for mixing the substances, the two substances are stored separately from one another, as a result of which the safety and/or shelf-life of the substances is increased. The initialization is only carried out before a planned application, in particular an injection, the stopper devices in the medicament container being displaced along a center axis of the medicament container into an axial position in which mixing is possible, in particular via a bypass.
In order to increase the sliding ability of the stopper devices in the medicament container and thus to achieve a safe medicament container which assures aseptic storage and/or application of a medical agent, the inner wall of the medicament container is siliconized. As a result, however, it is not possible, or at least not safe, to place in such known medicament containers substances which react on contact with the siliconized inner wall, in particular in an unintentional manner.
Temporally and/or spatially separated filling of the respective chambers is complicated, since the medicament container must be rotated and/or closed after filling the first chamber and/or the filling of the second chamber must be completed before the first chamber can be filled. In addition, mixing the two substances in such a medicament container is not optimal, particularly because of the typically small dimensions of the bypass.
In addition, with such conventional stopper devices it is not possible, or it is only possible under difficult conditions, to design an ampule or injection bottle, also called a vial, as a multi-chamber system, in particular a double-chamber system, since these vessels are embodied open only at one end. Thus, when axially sealing stopper devices are displaced in such vessels, pressure fluctuations occur which make displacement in the axial direction more difficult and ultimately Date Recue/Date Received 2020-12-09

3 limit such displacement. In particular, the second stopper device functioning as a center stopper cannot easily be displaced far enough into such a vessel. In addition, in such vessels displacement of the second stopper device into the mixing position is not possible, or at least is significantly more difficult and therefore not practicable, because of the pressure fluctuations that result.
The object of the invention is to create a stopper device, a medicament container, and a method for mixing two substances in a medicament container, wherein the aforesaid disadvantages are avoided. In particular, it is the object of the invention to create a medicament container and a stopper device in which unstable substances, in particular powder medicines which must not come into contact with a siliconized inner wall, can be safely stored and mixed with a second substance.
The object is achieved by creating the subject matter of the independent claims. Advantageous configurations result from the subordinate claims.
The object is achieved in particular by creating a stopper device for sealing off a medicament container, the stopper device having a stopper element, wherein the stopper device is designed to seal off the medicament container in an axial direction of a center axis of the medicament container, in particular by means of the stopper element, wherein the stopper device is at least partially insertable into the medicament container and in the intended installation position in the medicament container the stopper element is displaceable along the center axis of the medicament container, and wherein the stopper device, in particular the stopper element, has a retention region with at least one retention means. The stopper device is distinguished in that, in a first functional state of the stopper device, a closure element is retained by means of the retention means in a fixed position relative to the stopper element, in particular retained releasably directly on the stopper element, in such a way that a cavity is formed between the closure element and the stopper element. In this way, a substance provided in particular for mixing can be arranged in this cavity of the stopper device and stored sealed off with respect to the surroundings without a medicament container being necessary for this purpose. A
medicament container can be filled with two substances in a simple manner in two separate steps that are largely independent of one another. It is also possible to safely store an unstable substance, in particular powder medicines, in such a stopper device, since contact with silicone, in particular a siliconized inner wall of a medicament container, is prevented. By means of such Date Recue/Date Received 2020-12-09

4 a stopper device, it is also possible and made simple to form a double-chamber system in an injection vial and/or ampule, since no center stopper is required for separating two chambers.
A substance is understood here in particular to be a medicinal substance, very particularly a medicinal active substance and/or adjuvant.
The stopper device, in particular the closure element and the stopper element, is/are embodied to receive such a substance, in particular a medicinal agent, in the cavity, preferably aseptically, the cavity preferably being fluidically tight. The stopper device preferably has a plastic or comprises plastic.
A stopper element is understood here to be a stopper, in particular an end stopper, for a medicament container. The stopper element preferably has an elastic material or comprises such a material. The stopper element particularly preferably comprises an elastomer and/or soft plastic. In a sealing region, the stopper element is preferably at least partially elastic and/or along a circumferential surface in the sealing region which, when in the intended installation position in a medicament container, faces an inner wall of the medicament container and/or an insertion sleeve and is positioned tightly against this, for sealing contact with the inner wall and/or the insertion sleeve. The medicament container is thus sealed in the axial direction, in particular by the tight contact of the stopper element and/or stopper device against an inner wall of the medicament container, so that at least one chamber of the medicament container designed for receiving a substance is delimited in the axial, preferably proximal direction.
A medicament container is understood here to be in particular a syringe, carpule, ampule and/or injection bottle, a so-called vial. Such medicament containers, in particular syringes and carpules, are embodied as a single-chamber system or multi-chamber system, in particular a dual-chamber system.
The stopper device and/or the stopper element are preferably at least partially insertable, particularly preferably completely insertable, into the medicament container.
In the inserted state, that is, in the intended installation position in the medicament container, the stopper element can preferably be displaced along the center axis by means of a piston rod and/or a dispensing device.
Date Recue/Date Received 2020-12-09 The retention means in the retention region is preferably embodied integral with the stopper element. The retention means preferably has a region that is elastic in the radial direction, so that in the first functional state the closure element is retained by means of radial retaining forces.
The retention means and the stopper element particularly preferably comprise an elastic material,

5 in particular rubber and/or soft plastic.
In the first functional state, the closure element is preferably retained in the retention position such that it is not possible to displace the stopper element without simultaneously displacing the closure element. There is thus preferably a mechanical contact between the stopper element and the closure element, at least in the first functional state of the stopper device.
According to a further development of the invention, it is provided that in the first functional state the cavity is fluidically sealed off with respect to a wall, in particular the inner wall, of the medicament container. Contact with a siliconized surface is thus prevented and the safety for a substance stored in the cavity is high.
In the first functional state, the cavity is preferably delimited exclusively by the closure element .. and the stopper element and is embodied thereby. It is provided in particular that the cavity is embodied by a hollowing in the stopper element and/or in the closure element, the cavity being closable by means of the closure element, in particular being closed in the first functional state.
The closure element thus seals off the cavity, so that a substance stored therein is fluidically sealed off with respect to surroundings, in particular with respect to the medicament container. In .. particular, a fluidic seal with respect to an inner wall of a medicament container is created given the installation position in the medicament container is as intended. Thus, a tight cavity for safe storage of a substance is created even without a medicament container.
According to a further development of the invention, it is provided that in a second functional state the cavity is open, wherein the closure element is not retained in the retention position by the retention means. It is thus possible to open the cavity and therefore to cause a first substance stored therein to mix with a second substance stored in a chamber of a medicament container.
When the stopper device is in the intended installation position in the medicament container, in the second functional state the cavity is thus open in particular with respect to the chamber of the medicament container, wherein there is a fluidic connection between the cavity and the chamber in which the second substance is preferably stored. Mixing of two substances, in particular the Date Recue/Date Received 2020-12-09

6 first substance and the second substance, can thus be carried out simply and safely in a medicament container with such a stopper device.
Alternatively, however, it is also possible that in the second functional state the closure element is not completely released by the retention means, but instead continues to be retained at least partially on the stopper element, in particular in the retention region, wherein the closure element however no longer seals off the cavity, so that there is a fluidic connection to the outside of the cavity, in particular into the chamber of the medicament container.
As an alternative or in addition, it is provided that even when the stopper device is not inserted in the medicament container, in the first functional state the closure element is retained in a fixed position with respect to the stopper element. Thus, the stopper device can be used flexibly and a medicament container for safe storage of the first substance in the stopper device is not required.
The stopper element of the stopper device is particularly preferably embodied as an end stopper for a medicament container, wherein it is provided that the stopper device and, at least in the first functional state, the stopper element are arranged at the end, in particular at the proximal end, of a chamber of a medicament container. An end stopper arranged at the end in a medicament container is understood here to mean in particular a stopper that seals off the medicament container, wherein all of the in particular medicinal substances included in the medicament container and/or all of the chambers designed for them are arranged proceeding from the stopper in the distal direction. On the other hand, proceeding from the end stopper arranged at the end in the proximal direction, no chambers or regions are provided which are designed for safely storing a substance, in particular a medicinal substance. Thus, such an end stopper separates an aseptic region provided distal to the end stopper from a region provided proximal to the end stopper, which region is only subject to lower cleanliness requirements, in particular no cleanliness requirements.
According to a further development of the invention, it is provided that the closure element is embodied as a mixing body, in particular as a ball, for the medicament container and/or, in the second functional state, is arranged in the medicament container so that it can move freely, in particular independently of the stopper element. In the second functional state, the in particular spherical closure element is preferably arranged loose in the medicament container. This improves the mixing of the first substance with the second substance by shaking the medicament container, the mixing body causing additional turbulence in the medicament container.
Date Recue/Date Received 2020-12-09

7 According to a further development of the invention, it is provided that, in the first functional state, the stopper element has a discharge projection on its side facing the closure element and the discharge projection is at least partially oriented in the direction of the closure element. The discharge projection can be embodied elastic at least in a longitudinal direction along a center axis when in the intended installation position in a medicament container, but it is so stable that the closure element can be displaced by the discharge projection out of the retention position, in which the cavity is tightly closed, in an axial direction, in particular in the distal direction of the medicament container, wherein the retention forces applied by the retention means are overcome. An axial resistance force, that is, the strength of the discharge projection, which counteracts an axial deformation of the discharge projection, is therefore greater than the retention force applied by the retention means.
An axial force required to move the closure element out of the retention position, in particular in the distal direction, is preferably applied to the piston rod by a piston rod and manual pressure.
The discharge projection preferably projects in the distal direction. Thus, even after positioning in the medicament container, the closure element can be moved out of the retention position in a simple manner and the stopper device can thus be transitioned to the second functional state. The cavity and the substance arranged therein, and, when in the intended installation position in a medicament container, the chamber of the medicament container and the second substance stored therein are fluidically sealed off, in particular in a sterile manner, with respect to the .. surroundings of the medicament container, which is in particular closed with a cap.
When arranged as intended in the rotationally symmetrical, in particular at least substantially cylindrical medicament container, the discharge projection is preferably arranged concentric with a longitudinal axis of the medicament container. Thus, the forces to be applied in the distal direction are minimal and the seal between the stopper device and an inner wall of the .. medicament container is particularly high due to the symmetry formed thereby.
An outer wall of the stopper element in the retention region is preferably offset radially inward compared to an outer wall in the sealing region, so that, when in the intended installation position in a medicament container, circumferential free space is formed between the stopper element and the inner wall of the medicament container to allow the retention means to divert.
Due to the free space, it is easy to remove the closure element from the retention region, since the material of the stopper element in the retention region does not have to be compressed as strongly, but instead only has to be deformed into the free space.
Date Recue/Date Received 2020-12-09

8 According to a further development of the invention it is provided that, at least in an ejection state of the stopper device, but preferably also in the first functional state, a side and/or tip and/or end face of the discharge projection facing the closure element is positioned against the closure element. The ejection state thus denotes the state of the stopper device in which the closure element is still in the first functional state, but would transition immediately to the second functional state through a minimal force on the stopper device in the distal direction and a pressure exerted thereby from the discharge projection onto the closure element. The ejection state is thus the limit state between the first functional state and the second functional state. The forces to be applied in the distal direction are thus minimal and the closure element is moved out of the retention region in a particularly controlled manner.
According to a further development of the invention, it is provided that the closure element has at least one first locking means, wherein the retention means of the stopper device has at least one second locking means embodied to correspond to the first locking means and arranged in the retention region on a side of the stopper element facing the closure element, wherein, in the first functional state, the first locking means and the second locking means engage in one another in a locking manner. The closure element is thus securely held on the stopper element.
The closure element preferably has at least one locking receptacle, in particular a ring-like circumferential locking groove, wherein the retention means of the stopper device has at least one locking projection embodied corresponding to the locking receptacle, which is arranged in the retention region on a side of the stopper element facing the closure element, wherein, in the first functional state, the locking projection engages in the locking receptacle. In this case, therefore, the first locking means is embodied as a locking receptacle and the second locking means as a locking projection. When the stopper device is in the intended installation position in the medicament container, the locking receptacle is preferably embodied in the circumferential direction about a center axis of the medicament container. The closure element is thus held in the retention position in a particularly reliable manner.
Alternatively, however, it is also possible for the first locking means to be embodied as a locking projection and the second locking means as a locking receptacle, so that the retention means has the locking receptacle and the closure element has the locking projection. In this case, as well, the closure element is securely held in the retention position.
Date Recue/Date Received 2020-12-09

Claims

PCT/EP2019/067479

1.

Stopper device (1) for sealing off a medicament container (45), with a stopper element (3), 5 wherein the stopper device (1) is embodied to seal off the medicament container (45) in an axial direction of a center axis (M) of the medicament container (45), wherein the stopper device (1) is at least partially insertable into the medicament container (45) and in the intended installation position in the medicament container (45) the stopper element (3) is displaceable along the center axis (M) of the medicament container (45), characterized in that the stopper device (1) 10 has a retention region (23) with at least one retention means (5), wherein, in a first functional state of the stopper device (1), a closure element (7) is releasably retained in a fixed position relative to the stopper element (3) by means of the retention means (5), in particular on the stopper element (3), in such a way that a cavity (29) is formed between the closure element (7) on the one hand and the stopper element (3) on the other hand.
15 2. Stopper device (1) according to claim 1, characterized in that in the first functional state the cavity (29) is fluidically sealed off with respect to a wall, in particular an inner wall (53), of the medicament container (45).

3. Stopper device (1) according to one of the preceding claims, characterized in that in a second functional state the cavity (29) is open, wherein the closure element (7) is not retained in 20 the retention position by the retention means (5).

4. Stopper device (1) according to one of the preceding claims, characterized in that the closure element (7) is embodied as a mixing body for the medicament container (45) and/or, in the second functional state, is arranged freely movable in the medicament container (45).

5. Stopper device (1) according to one of the preceding claims, characterized in that, in the 25 first functional state, the stopper element (3) has a discharge projection (63) on its side facing the closure element (7) and the discharge projection (63) is at least partially oriented in the direction of the closure element (7).
Date Recue/Date Received 2020-12-09

6. Stopper device (1) according to one of the preceding claims, characterized in that, at least in an ejection state of the stopper device (1), the discharge projection (63), with a side and/or tip facing the closure element (7), is positioned against the closure element (7).

7. Stopper device (1) according to one of the preceding claims, characterized in that the closure element (7) has at least one first locking means, wherein the retention means (23) of the stopper device (1) has at least one second locking means embodied corresponding to the first locking means and arranged in the retention region (23) on a side of the stopper element (3) facing the closure element (7), wherein, in the first functional state, the first locking means and the second locking means engage in one another in a locking manner.

8. Stopper device (1) according to one of the preceding claims, characterized in that the stopper device (1) has an insertion sleeve (15) enveloping the stopper element (3), wherein an outer side of a sleeve wall is preferably embodied for tight contact against an inner wall (53) of the medicament container (45).

9. Stopper device (1) according to one of the preceding claims, characterized in that the insertion sleeve (15) is designed as a finger rest and has at least one radially protruding finger plate (19) at a proximal end, which finger plate (19) can be grasped from behind by a finger.

10. Stopper device (1) according to one of the preceding claims, characterized in that the insertion sleeve (15) has a fastening structure (41) for fastening the insertion sleeve (15) to the medicament container (45), wherein the fastening structure (41) preferably has a receptacle (43) for the medicament container (45), in which receptacle (43) the proximal end (49) of the medicament container (45) can be received in a locking and/or clamping manner.

11. Medicament container with a base body (47) and a stopper device (1) according to one of the preceding claims, wherein the stopper device (1) is arranged moved into the medicament container (45) such that the stopper element (3) seals off a proximal end (49) of the medicament container (45) with respect to a chamber (51) of the base body (47), wherein the chamber (51) is delimited in the radial direction by an inner wall (53) of the base body (47) and in the distal direction by an outlet opening (55) of the base body (47) and/or a closure cap (57).

12. Medicament container according to claim 11, characterized in that the outlet opening (55) of the base body (47) has a geometry, in particular a cruciform cross-section (60), at least on its Date Recue/Date Received 2020-12-09 side facing the chamber (51), which differs from a side of the closure element (7) facing the outlet opening such that a fluidically tight closure of the outlet opening (55) is prevented by the closure element (7).

13. Medicament container according to claim 11 or 12, characterized by a dispensing device (67), wherein a projection (73) is provided at a distal end (71) of the dispensing device (67).

14. Medicament container according to one of claims 11 to 13, characterized in that the stopper element (3) is elastic, wherein it is deformable by means of the projection (73) of the dispensing device (67), in particular using manual exertion of pressure on the dispensing device (67) in the distal direction, wherein the discharge projection (63) of the stopper element (3) has a .. greater strength in the axial direction than the pressure required to move the closure element (7).

15. Method for mixing two substances (31, 59) stored separately from one another in terms of flow in a medicament container (45) according to one of claims 11 to 14 with a stopper device (1) according to one of claims 1 to 10, wherein a first substance (31) of the two substances (31,59) is arranged in the cavity (29) of the stopper device (1) and a second substance (59) of the two substances (31,59) is arranged in the chamber (51) of the base body (47), wherein the stopper element (3) is acted upon with a force in the distal direction, wherein the fluidic separation of the two substances (31, 59) is eliminated, characterized in that the stopper device (1), in particular the stopper element (3), is deformed, at least partially, due to the distal force application, such that the closure element (7) is moved out of the retention position.

16. Method according to claim 15, characterized in that the stopper element (3) is displaced in the distal direction, wherein the fluidic separation of the two substances (31, 59) is eliminated, wherein the retention region (23) relaxes radially during the distal displacement of the stopper device (1), and wherein the retention of the closure element (7) in the retention position is released.

17. Method according to claim 15 or 16, characterized in that the medicament container (45) is shaken after the cavity (29) has been opened.

18. Method according to one of claims 15 to 17, characterized in that the stopper device (1) is displaced into an end position for the complete discharge of the two substances (31, 59) in the Date Recue/Date Received 2020-12-09 medicament container (45), wherein the closure element (7) is received in the end position in the cavity (29), and wherein the cavity (29) is completely filled by the closure element (7).
Date Recue/Date Received 2020-12-09